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Date of Award


Document Type

Thesis - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)


Graduate School

First Advisor

David S. Fries

First Committee Member

James W. Blankenship

Second Committee Member

Madhukar Chaubal

Third Committee Member

Alice Jean Matuszak

Fourth Committee Member

Charles A. Matuszak


Previous studies active-site-directed metal coordinating reagents and substrate analogues of (N8-AcSpd) have indicated that the catalytic mechanism of N8-AcSpd deacetylase involved a transition state metal. Several ω-amino substituted carboxylic acids were tested and results confirmed the probability of the deacetylase having a mechanism similar to the metalloproteases. Based on these results, several analogues of spermidine containing metal coordinating ligands were designed and synthesized. In addition, a potential transition state analogue of the nuclear enzyme, spermidine N8-acetyltransferase (N8-SAT) was also synthesized. All compounds were assayed in a 100,000g cytosol fraction form rat liver for their ability to inhibit the acetylation of radiolabeled substrate, [acetyl-3H]-N8-AcSpd. The apparent Ki (app Ki) values were determined from Dixon plots. The apparent Km of N8-AcSpd for the cytosolic deacetylase is 11.0 μM.

Based on the results of this investigation and results obtained earlier in this laboratory, hypothetical models for the binding interactions of substrates and inhibitors to the active sites of N8-AcSpd deacetylase and N8-SAT are drawn schematically. The mechanism of catalysis of N8-AcSpd deacetylase also is proposed.



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